Levo-1-phenyl-2-methyl-ethylamino propanol-1 and acid addition salts thereof and process for making them



Patented Mar. 11, 1941 ENYL-t-METHYL-ETHYLAMINO one one son) ADDITION SALTS nan raoosss son MAKING TENT l lo Drawing. Application mecenihcr 2, 1938, Serial No. tithes "1 claims.

This invention relates to the N-ethyl derivative oi levo l-phenyl 2-rnethylamino propan-l-ol, and includes this new product and an advantageousniethod oi preparing it and other products.

m The levo-rotatory compound l-ephedrlne, is an extremely valuable therapeutic agent widely used for the treatment of asthma, hay fever, etc., and as vaso-constricting agents for the treatment oi colds and the lilre. The most commonly used product is natural l-ephedrine, which is commonly obtained from the plant Mal-luring, although it is also prepared synthetically. Synthetlc l-phenyl z-methylamino propan-i-ol is produced as a racemic mixture of ephedrine-d1 and pseudo-'ephedrine-dl. This racemic mixture has properties and uses similar to those of lephedrine, but has a much lower activity than lephedrine. It may be resolved into the levoand dextro-iractio-ns; and the levo-ephedrine separated which is quite comparable with the naturally occurring allraloid. L-pseudo-ephedrims and d-pseudo-ephedrine, which are other stereoisomerlc forms of l-phenyl Z-rnethylamino propan-l-ol are also available as alkaloids having more or less similar properties. The use oi lphenyl t-methylan'iino propan-l-oi, for example, hy internal administration ior relief in asthma, is subject to certain disadvantages because oi side effects, as in many cases it causes sleeplessness, nausea, albuminurea, palpitations oi the heart, etc.

The new l-phenyl z-inethylamino propan-lpl derivatives of the present invention have some oil the same therapeutic properties as the products referred to above, e. g. for the treatment of asthma, etc, but have a greatly reduced tendency to cause side effects, including circulatory and general systemic disturbances.

The new derivative of the present invention is the levo l-phenyl 2-methylethylamino propan-l-= oi (CcH5CHUHCH(CH3NC2H5)(3H3). The prodnot is a tertiary amine, obtained by replacing the till dil

til

nitrogen-linked hydrogen of levo l-phenyl 2- methylamino propan-l-ol by an ethyl group, advantageously by reaction with diethyl sulfate.

The new product may be prepared in the form of the free base, or in the form of acid addition salts, such as the hydrochlorides. the sulfates, the phosphates, the picrates, the oleates or other fatty acid salts, etc. For internal administration, as in the treatment of asthma. or the like, the salts, particularly the hydrochloride, sulfate or am phosphate, are used.

it'll. Edit-57%) in preparing the new derivative of the invention, levo 1-phenyl 2-methylamlno propan-l-ol, is ethylated with .a suitable ethylatlng agent, advantageously diethyl sulfate, with the direct production of the corresponding ethyl salt. The cthyl group is introduced on the nitrogen atom, rather than on the hydroxyl group, with the production of the tertiary amine. The salt obtained is readily converted to the free base by suitable treatment with alkali, and any oi the acid addition salts are readily prepared from the free base by simple neutralization. The new product may also he prepared with the use of other ethylating agents, such as ethyl iodide or ethyl bromide. ll-ethyl derivatives oi" the other (stereo or geometrical isomers oi the levo compound) lphenyl iz-methyletl'iyl amino propan-l-ols maybe similarly prepared.

The production oi the new derivatives will be illustrated by the following example, but it is not limited thereto.

Example-fi l parts of l-ephedrine are dissolved in about til parts of alcohol. to parts of redistilled diethyl sulfate are then slowly added over a period oi about three-fourths to one hour, while maintaining the temperature at till-till G. litter the addition of the ethyl dlsuliate is complete, the mixture is maintained for about twohours longer at til-5d U. The solvent is then distilled oil at a reduced pressure and the residual viscous oil is shalren with to parts oi ch72, potassium hy drorride solution. The tree hase is eutracted from this mixture hy treatment with three successive portions oi ether. The ether is evaporated from the combined extract and an aqueous, saturated solution of oxalic acid is added to the resulting thiclr oil until the nihrture is acid to litmus. When the resulting solution is chilled, the unre acted ephedrine separates as an insoluble oxalate, the i-l l ethyl ephedrine oxalate remaining in solution. This soluble oiralate is then shaken with to parts of all% potassium hydroxide solution and the free base is extracted with ether. The other solution is dried over sodium sulfate and the other is removed by evaporation. The levo-l-phenyl 2-methylethylamlno propan-l-ol is obtained in excellent yields, while substantially all of the unreacted l-ephedrine is recovered as the insoluble oxalate.

The new levo-l-phenyl .i-methylethylamino propan-l-ol is a white crystalline solid, M. P. 29- 30 C. It is relatively soluble in mineral oil, one part dissolving in ten parts oi oil to give a clear til .solution and in six parts o! oil to give an opalescent solution. Its specific rotation line plcrate, M. P. -111; a white crystalline ethiodide, M. P. -167 0., specific rotation a crystalline hydrochloride, M. 1?. 0., specific rotation in water; a crystalline phosphate, R.H:P04, M. P. 230? C., specific rotation in water. It readily i'orms acid addition salts with other acids, including inorganic acids such as sulfuric acid, other halogen and phosphoric acids, etc., and organic acids, including the lower and higher fatty acids, such as acetic, propionic, lauric, oleic, stearic acids, etc., lactic acid, succinic acid, etc.

Pharmacological tests indicate that this compound has substantially the same toxicity as lephedrine. Some therapeutic properties, as indicated, for example, by dilation of the bronchioles, are about the same as that of ephedrine. It has important advantages over-ephedrine in that, in therapeutic doses, it has a negligible effect upon blood pressures, apparently producing at the most a transient drop in blood pressure lasting several seconds followed by a return to normal pressure, whereas ephedrine produces, in

35 therapeutic dosage, a substantial rise in blood pressure. This rise in blood pressure is one of the most important deleterious clients 01 l-ephedrlne when used as a therapeutic agent, and is indicative oi the circulatory and general systemic disturbances caused by l-ephedrlne; and one of the important advantages of the new product is that, in therapeutic dosage, it causes no substantial efi'ect on blood pressure.

I claim:

1. The process of preparing l-phenyl 2-methyl-ethylamino propan-l-ol which comprises reacting l-phenyl Z-methylamino propan-l-ol with diethyl sulfate and recovering unreacted i-phenyl z-methylamino propan-l-ol from the reaction product by precipitation from aqueous solution as the oxalate.-

2. Levo-l-phenyi 2-methylethylamino propan- 1-01.

3. Acid addition salts oi levo-l-phenyl 2-methylethylamino propan-l-ol.

4. Levo-l-phenyl 2-methylethylamino propanl-ol hydrochloride.

5. Levo-l phenyl Z-methylethylamino propanl-ol phosphate.

6. Compounds of the class consisting of levo-lphenyl 2-methylethylamino propan-i-ol and its acid addition salts.

7. The process of preparing levo-i-phenyl 2- methylethylamino propan-l-ol which comprises reacting i-phenyl Z-methylamino propan-l-ol with diethyl sulfate and recovering unreacted levo-i-phenyl' 2-methylamino propan-l-ol from the reaction product by precipitation from aqueone solution as the oxalate.

ROBERT S. BHELTON. 

